The present invention relates to the field of ocular disorders.
In the eye, scarring obstructs vision. Worldwide, ocular scarring is the leading cause of monocular blindness. Initial wound healing responses prevent infection but subsequent tissue repair must result in regenerative healing to prevent the development of blinding scar tissue in the eye.
Glaucoma is a disease where extracellular matrix accumulates in the trabecular meshwork, decreasing aqueous outflow and increasing pressure in the eye. Increased integrin-mediated cell adhesion of trabecular meshwork cells contributes to this transformation.
The surgery to relieve the pressure that is associated with Glaucoma is a trabeculectomy surgery. The “bleb” or flap that is made to relieve pressure often heals with a scar, reversing the benefit of the surgery. Currently mitomycin C treatment is used to halt all cell proliferation after surgery in an effort to stop this scarring outcome. This treatment is unpredictable and has safety concerns. The cells that proliferate and differentiation are called tenon fibroblasts.
Another major point of fibrotic scarring in the eye is in the layer of epithelial cells called Retinal Pigmented Epithelial cells (RPE). The RPE layer of cells is adjacent to the retina. They are critical to vision and the correct functioning of the retina. The migration and proliferation of the RPE cells is called epithelial to mesenchymal transition (EMT), which leads to the development of fibrotic RPE myofibroblasts and a thick disorganized extracellular matrix covering the retina. Major diseases that either derive from or end with fibrotic outcomes in the RPE layer are age-related macular degeneration, diabetic retinopathy, and proliferative vitreoretinopathy.
Age-related macular degeneration (AMD) is the loss of photoreceptors in the central retina. Degeneration of the macula is associated with abnormal deposition of extracellular matrix called Drusen in the membrane between the RPE and the vascular choroid inducing a fibrovascular subretinal membrane leading to retinal scarring.
Proliferative Diabetic Retinopathy (PDR) is the more advanced stage of Diabetic Retinopathy, a disorder that develops in diabetic patients typically after a decade with the disease. An over accumulation of sugars damages the blood vessels in the retina. PDR is characterized by neovascularization into the retina. New aberrant blood vessels leak blood and growth factors that induce EMT ending in the development of fibrotic RPE myofibroblasts and a thick disorganized extracellular matrix covering the retina. This leads to retinal detachment.
Proliferative vitreoretinopathy (PVR) occurs after mechanical retinal detachment, fluid from the vitreous humor enters a retinal hole. During this process the RPE comes in contact with vitreous cytokines that induces EMT (fibrotic epithelial-derived myofibroblasts), which secrete disorganized extracellular matrix and fibrotic cytokines. This leads to scarring of the retina.